Obesity linked to inflammation and organ transplant rejection

A transplant surgical team at work at the Center for Care and Discovery at the University of Chicago Medicine. (Photo by Robert Kozloff)

One of the reasons obesity is so dangerous for long-term health is that it produces low-grade, chronic inflammation. This kind of inflammation revs up the immune system, which can aggravate other chronic conditions like asthma, high blood pressure, and digestive disorders.

A recent study by researchers at the University of Chicago suggests that obesity increases the risk of organ transplant rejection as well. It’s a troublesome finding when more and more transplant recipients are likely to be overweight, putting them at greater risk in an already precarious state of health.

In the study, published this month in the journal Transplantion, Maria-Luisa Alegre, MD, PhD, Anita Chong, PhD, and their team used a model with obese mice that had been fed a high-fat diet to mimic the kind of obesity that causes inflammation and metabolic issues in humans. The obese mice rejected transplanted hearts more quickly than lean mice on a low-fat diet, and showed stronger activity of T-cells that carry out the immune response to reject the organ.

Just how obesity exacerbates the immune response to the organ isn’t clear yet, however, a process Alegre says is still a “black box.”

Marisa Alegre, MD, PhD

“There are many things that are changing in the body during obesity, including low grade inflammation, higher levels of blood glucose and lipids, and different types of commensal microbes colonizing the body,” Alegre said. “Whether and how these or other changes affect the immune response that rejects the graft is the link that we don’t yet have.”

In obese individuals, adipocytes, or fat cells, become enlarged and undergo stress. These adipocytes produce cytokines, proteins that give signals to other cells, which rev up the immune system. These cytokines could be triggering the stronger T-cell response to the transplanted organ. Obese individuals also tend to have higher levels of cholesterol, lipids, and glucose circulating in the blood, all of which could enhance the immune response against the transplant.

Another intriguing possibility is the role played by the microbiota, or the millions of bacteria and other microorganisms living in the digestive tract and other body surfaces. Previous research has shown that obesity can change the composition and behavior of these microbiota—it’s possible that these changes affect how the microbiota interact with immune cells that recognize the antigens introduced by the organ transplant. This could in turn affect the level of tolerance the immune system has for these antigens, and speed up the rejection process.

Alegre and her team are continuing to study how the microbiota influences the immune system, and how changes wrought by obesity could lead to a heightened rejection response. It may be possible to develop treatments that manipulate the microbiome in a way that reduces inflammation before and after a transplant to improve the chances of graft survival.

Until then, the grim reality of a chronic shortage of donor organs combined with increasing numbers of obese patients, means that doctors will have to work around the added risk.

“Unfortunately for the recipients, there is such a shortage of organs,” Alegre said. “It’s just a reality of our population that we have a lot of patients who are overweight, and we need to monitor them carefully.”